Allosteric modulation of heterodimeric G-protein-coupled receptors

doi:10.1016/j.tips.2007.11.001

Trends in Pharmacological Sciences

Volume 28, Issue 12, December 2007, Pages 615-620

https://doi.org/10.1016/j.tips.2007.11.001 Get rights and content

G-protein-coupled receptors (GPCRs) are, and will probably remain, the most tractable class of targets for the development of small-molecule therapeutic medicines. Currently, all approved GPCR-directed medicines are agonists or antagonists at orthosteric binding sites – except for the calcimimetic cinacalcet, which is a positive allosteric modulator of Ca²⁺-sensing receptors, and maraviroc, an allosteric inhibitor of CC-chemokine receptor (CCR) 5. It is now widely accepted that GPCRs exist and might function as dimers, and there is growing evidence for the physiological presence and relevance of GPCR heterodimers. Molecules that can regulate a GPCR within a heterodimer, through allosteric effects between the two protomers of the dimer or between a protomer or protomers and the associated G protein, offer the potential to function in a highly selective and tissue-specific way. Despite the conceptual attraction of such allosteric regulators of GPCR heterodimers as drugs, they cannot be identified by screening approaches that routinely use a ‘one GPCR target at a time’ strategy. In our opinion, this will require the development of new approaches for screening and a return to the use of physiologically relevant cell systems at an early stage in compound identification.

Section snippets

Allosterism and cooperativity

It is frequently noted that G-protein-coupled receptors (GPCRs) are the most tractable class of receptors for drug design and direct targets of ∼30% of clinically prescribed, small-molecule medicines 1, 2. Nonchemosensory GPCRs are encoded by ∼350 genes in humans [3]. However, <40 GPCRs are truly validated therapeutic targets, in that they have been determined as the site of action of these medicines. With the exceptions of cinacalcet, which functions as a positive allosteric modulator (see

The conundrum

Because GPCRs have historically been treated as monomeric, noninteracting polypeptides, the current focus on allosteric modulators centres on molecules that alter the binding or function of orthosteric ligands by binding the same (monomeric) GPCR. This has been described as ‘in-target’ allosterism (Figure 1) [10]. Dimerization or oligomerization of proteins is, however, an extremely common theme in biology [11]. If, as seems probable, most GPCRs exist and function as constitutively formed

The potential of heterodimerization of G-protein-coupled receptors

There is currently particular interest in, and debate on, the generality and physiological relevance of heterodimerization of GPCRs, in which two distinct GPCRs interact physically, and the potential of these GPCR heterodimers to provide novel therapeutic targets [13]. If a GPCR heterodimer is considered as a constitutively formed, single functional unit, the binding of a ligand at any site in protomer 2, including the orthosteric site, can potentially alter the pharmacology and function of

Do G-protein-coupled receptor heterodimers exhibit novel pharmacology and function?

There seems little doubt that this question can be answered in the affirmative (reviewed in Ref. [13]). In a far larger number of cases than can be considered herein, coexpression of pairs of GPCRs that have the capacity to heterodimerize results in unique pharmacology. This has been studied most extensively using coexpression of pairs of opioid receptors. For example, if mu opioid peptide (MOP) and delta opioid peptide (DOP) receptors were coexpressed, a series of highly selective synthetic

Allosteric modulation of heterodimeric G-protein-coupled receptors

According to the above, GPCR heterodimers might be anticipated to be particularly suitable targets for selective allosteric modulation. In addition to allosteric effects arising from two ligands binding at different sites of the same GPCR protomer, a ligand that binds orthosterically at protomer 1 of a GPCR heterodimer can be anticipated to modulate allosterically the function of a ligand binding orthosterically at protomer 2 of the heterodimer (Figure 1). This can only occur in cells that

Allosteric modulation of heterodimeric family C G-protein-coupled receptors

The sweet and umami taste receptors are of great interest to the flavour and food industries; they are physiologically defined GPCR heterodimers 29, 30, comprising the (sweet) taste receptor type 1 member 2 (T1R2) and taste receptor type 1 member 3 (T1R3) and (umami) taste receptor type 1 member 1 T1R1 and T1R3 pairings of individual family C, metabotropic glutamate-like GPCR gene products. Whereas the artificial sweetener aspartame is an orthosteric agonist that binds at the large,

Interactions between orexin-1 receptors and cannabinoid CB1 receptors

In 2006, Acomplia^® (manufactured by Sanofi Aventis) was approved in Europe for the treatment of obesity in overweight individuals who have a body-mass index >30 kg/m² [32]. Also known as ‘rimonabant’ or ‘SR141716A’, this ligand is clearly an orthosteric antagonist or inverse agonist of the CB1 receptor [33]. Because of the known proappetite effects of CB1 receptor agonists, this might be sufficient to fully explain its clinical effectiveness. However, because of the overlapping distribution of

Concluding remarks

Several GPCR-directed therapeutic ligands are known to interact with more than one GPCR. Although in several examples the contribution of this function to clinical effectiveness is unclear or has only been rationalized post hoc, in certain cases such polypharmacology might be designed into ligands deliberately, for example in efforts to design ligands that can block both CXC-chemokine receptor (CXCR) 4 and CCR5 as effective anti-HIV treatments [34] and combine the functions of muscarinic

Acknowledgements

G.M. thanks the Biological Sciences and Biotechnology Research Council, the Medical Research Council and the Wellcome Trust for financial support. N.J.S. is the recipient of a National Health and Medical Research Council of Australia and National Heart Foundation C.J. Martin Overseas Fellowship.

Glossary

Allosteric binding site: A binding pocket or other location on a GPCR distinct from the orthosteric site (see below). Although endogenous ligands might bind at these sites, allosteric sites are generally associated with binding synthetic chemical ligands.
Allostery: The mutual effect(s) of binding two (or more) distinct ligands at different sites on a protein or protein complex. Such effects can be positive or negative.
Cooperativity: The effect(s) of multiple equivalents of the same ligand binding to

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Trends in Pharmacological Sciences

OpinionAllosteric modulation of heterodimeric G-protein-coupled receptors

Section snippets

Allosterism and cooperativity

The conundrum

The potential of heterodimerization of G-protein-coupled receptors

Do G-protein-coupled receptor heterodimers exhibit novel pharmacology and function?

Allosteric modulation of heterodimeric G-protein-coupled receptors

Allosteric modulation of heterodimeric family C G-protein-coupled receptors

Interactions between orexin-1 receptors and cannabinoid CB1 receptors

Concluding remarks

Acknowledgements

Glossary

Pharmacol. Ther.

Drug Discov. Today

Trends Pharmacol. Sci.

Drug Discov. Today: Therapeutic Strategies

Trends Biochem. Sci.

Biochim. Biophys. Acta

Drug Discov. Today

Trends Biochem. Sci.

Cell. Signal.

J. Biol. Chem.

J. Biol. Chem.

J. Biol. Chem.

Trends Pharmacol. Sci.

J. Biol. Chem.

Lancet

J. Biol. Chem.

Drug Discov. Today

The druggable genome

Nat. Rev. Drug Discov.

The 7 TM G-protein-coupled receptor target family

ChemMedChem

Opinion
Allosteric modulation of heterodimeric G-protein-coupled receptors